The mature red blood cell, or erythrocyte, is responsible for oxygen transport in the circulatory systems of vertebrates. Red blood cells contain high concentrations of hemoglobin, a protein that binds to oxygen in the lungs at relatively high partial pressure of oxygen (pO2) and delivers oxygen to areas of the body with a relatively low pO2.
Mature red blood cells are produced from pluripotent hematopoietic stem cells in a process termed erythropoiesis. Postnatal erythropoiesis occurs primarily in the bone marrow and in the red pulp of the spleen. The coordinated action of various signaling pathways controls the balance of cell proliferation, differentiation, survival, and death. Under normal conditions, red blood cells are produced at a rate that maintains a constant red cell mass in the body, and production may increase or decrease in response to various stimuli, including increased or decreased oxygen tension or tissue demand. The process of erythropoiesis begins with the formation of lineage committed precursor cells and proceeds through a series of distinct precursor cell types. The final stages of erythropoiesis occur as reticulocytes are released into the bloodstream and lose their mitochondria and ribosomes while assuming the morphology of mature red blood cell. An elevated level of reticulocytes, or an elevated reticulocyte:erythrocyte ratio, in the blood is indicative of increased red blood cell production rates.
In general, anemia is a condition that develops when a subject's blood lacks enough healthy red blood cells or less than the normal quantity of hemoglobin. Anemia may also be diagnosed when there is decreased oxygen-binding capacity of red blood cells, which may result from a deformity in one or more hemoglobin subunits. As human cells depend on oxygen for survival, anemia can result in a wide range of clinical complications including, e.g., tissue damage. For example, it has been reported that ulcers are the one of most common cutaneous manifestation of chronic anemia disorders, particularly in hemolytic anemias such as sickle-cell disease and thalassemia. See, e.g., Keast et al. (2004) Ostomy Wound Manage., 50(10): 64-70; Trent et al. (2004) Adv Skin Wound Care, 17(8): 410-416; J. R. Eckman (1996) Hematol Oncol Clin North Am., 10(6): 1333-1344; and Rassi et al. (2008) Pediatric Annals 37(5): 322-328. The underlying mechanism for ulcer formation in anemic patients has not been completely defined. However, it is believed that multiple complications of anemia contribute to ulcer development including, for example, ischemia, decreased nitric oxide bioavailability, vascular obstruction, thrombosis, and hypoxia. Id.
Ulcer healing in anemic patients is typically a slow process, and such patients are also at a high risk of recurrent ulceration. See, e.g., Keast et al. (2004) Ostomy Wound Manage., 50(10): 64-70; Trent et al. (2004) Adv Skin Wound Care, 17(8): 410-416; J. R. Eckman (1996) Hematol Oncol Clin North Am., 10(6): 1333-1344; and Rassi et al. (2008) Pediatric Annals 37(5): 322-328. Furthermore, most therapies have had limited success in the treatment of ulcers occurring in anemic patients.
Thus, it is an object of the present disclosure to provide alternative methods for treating or preventing ulcers associated with anemia.